The present invention relates generally to phenanthridine carbonyl compounds such as substituted phenanthridine carbonyl phenols and methods of using them.
The ability of ligands for the estrogen receptor to inhibit inflammatory gene expression and cause a reduction of cytokines, chemokines, adhesion molecules and inflammatory enzymes is well known. A common component of chronic inflammatory conditions is polymorphonuclear leukocyte and monocyte infiltration into the site of damage through increased expression of cytokines and adhesion molecules responsible for their recruitment. Overproduction of the cytokine interleukin (IL-6) has been associated with states of chronic inflammation (Bauer M. A., Herrmann F., Ann. Hematol., 1991, 62, 203). Synthesis of the IL-6 gene is believed to be induced by the transcription factor nuclear factor κB (NF-κB). Interference at this step in the inflammatory process can effectively regulate the uncontrolled proliferative process that occurs in these chronic conditions.
Activation of the estrogen receptor provides a means to treat the inflammatory component of diseases such as atherosclerosis, myocardial infarction (MI), congestive heart failure (CHF), inflammatory bowel disease and arthritis, in part by interfering with cytokine expression. Other therapeutic indications for these type of molecules include type II diabetes (Cefalu, J Womens Health & Gender-based Med. 2001, 10, 241; Yuan et al., Science, 2001, 293, 1673), osteoarthritis (Pelletier et al., Arthr. & Rheum., 2001, 44:1237; Felson et al., Curr Opinion Rheum, 1998, 10, 269) asthma (Chin-Chi Lin et. al., Immunol. Lett., 2000, 73, 57), Alzheiemer's disease (Roth, A. et. al.,; J. Neurosci. Res., 1999, 57, 399) and autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.
In view of the foregoing, there exists a need for the identification of ligands for the estrogen receptor and for methods of using the identified ligands to modulate the activity of the receptor and, preferably, treat disease.